Characteristics and birth outcomes of pregnant adolescents compared to older women: An analysis of individual level data from 140,000 mothers from 20 RCTs.

BACKGROUND: Adolescence is a critical period of maturation when nutrient needs are high, especially among adolescents entering pregnancy. Using individual-level data from 140,000 participants, we examined socioeconomic, nutrition, and pregnancy and birth outcomes for adolescent mothers (10-19 years) compared to older mothers in low and middle-income countries. METHODS: This study was conducted between March 16, 2018 and May 25, 2021. Data were obtained from 20 randomised controlled trials of micronutrient supplementation in pregnancy. Stratified analyses were conducted by age (10-14 years, 15-17 years, 18-19 years, 20-29 years, 30-39 years, 40+ years) and geographical region (Africa, Asia). Crude and confounder-adjusted means, prevalence and relative risks of pregnancy, nutrition and birth outcomes were estimated using multivariable linear and log-binomial regression models with 95% confidence intervals. FINDINGS: Adolescent mothers comprised 31.6% of our data. Preterm birth, small-for-gestational age (SGA), low birthweight (LBW) and newborn mortality followed a U-shaped trend in which prevalence was highest among the youngest mothers (10-14 years) and then reduced gradually, but increased again for older mothers (40+ years). When compared to mothers aged 20-29 years, there was a 23% increased risk of preterm birth, a 60% increased risk of perinatal mortality, a 63% increased risk of neonatal mortality, a 28% increased risk of LBW, and a 22% increased risk of SGA among mothers 10-14 years. Mothers 40+ years experienced a 22% increased risk of preterm birth and a 103% increased risk of stillbirth when compared to the 20-29 year group. INTERPRETATION: The youngest and oldest mothers suffer most from adverse pregnancy and birth outcomes. Policy and programming agendas should consider both biological and socioeconomic/environmental factors when targeting these populations. FUNDING: Bill and Melinda Gates Foundation (Grant No: OP1137750).

Improving the mental health of women intimate partner violence survivors: Findings from a realist review of psychosocial interventions.

BACKGROUND: Intimate partner violence (IPV) is highly prevalent and is associated with a range of mental health problems. A broad range of psychosocial interventions have been developed to support the recovery of women survivors of IPV, but their mechanisms of action remain unclear. METHODS: Realist review following a prospectively published protocol in PROSPERO (CRD42018114207) and reported using the Realist and Meta-narrative Evidence Synthesis: Evolving Standards (RAMSES) guidelines. RESULTS: Evidence was extracted from 60 reviews and triangulated in expert consultations. Mechanisms of action were categorised as either associated with intervention design and delivery or with specific intervention components (access to resources and services; safety, control and support; increased knowledge; alterations to affective states and cognitions; improved self-management; improved family and social relations). CONCLUSIONS: Findings suggest that psychosocial interventions to improve the mental health of women survivors of IPV have the greatest impact when they take a holistic view of the problem and provide individualised and trauma-informed support.

Does antenatal micronutrient supplementation improve children's cognitive function? Evidence from the follow-up of a double-blind randomised controlled trial in Nepal.

INTRODUCTION: Multiple Micronutrient (MMN) supplementation during pregnancy can decrease the proportion of infants born low birth weight and small for gestational age. Supplementation could also enhance children's cognitive function by improving access to key nutrients during fetal brain development and increasing birth weight, especially in areas where undernutrition is common. We tested the hypothesis that children whose mothers received MMN supplementation during pregnancy would have higher intelligence in early adolescence compared with those receiving Iron and Folic Acid (IFA) only. METHODS: We followed up children in Nepal, whose mothers took part in a double-blind Randomised Controlled Trial (RCT) that compared the effects on birth weight and gestational duration of antenatal MMN versus IFA supplementation. We assessed children's Full Scale Intelligence Quotient (FSIQ) using the Universal Non-verbal Intelligence Test (UNIT), and their executive function using the counting Stroop test. The parent trial was registered as ISRCTN88625934. RESULTS: We identified 813 (76%) of the 1069 children whose mothers took part in the parent trial. We found no differences in FSIQ at 12 years between MMN and IFA groups (absolute difference in means (diff): 1.25, 95% CI -0.57 to 3.06). Similarly, there were no differences in mean UNIT memory (diff: 1.41, 95% CI -0.48 to 3.30), reasoning (diff: 1.17, 95% CI -0.72 to 3.06), symbolic (diff: 0.97, 95% CI -0.67 to 2.60) or non-symbolic quotients (diff: 1.39, 95% CI -0.60 to 3.38). CONCLUSION: Our follow-up of a double-blind RCT in Nepal found no evidence of benefit from antenatal MMN compared with IFA for children's overall intelligence and executive function at 12 years.

Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries.

BACKGROUND: Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries. METHODS: This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ2 test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect. FINDINGS: Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75-0·96 vs 1·06, 0·95-1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74-0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87-0·97; p=0·03), and 6-month mortality (0·71, 0·60-0·86; p=0·04) in anaemic pregnant women (haemoglobin <110g/L) as compared with non-anaemic pregnant women. Multiple micronutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m2; RR 0·84, 95% CI 0·78-0·91; p=0·01). Initiation of multiple micronutrient supplements before 20 weeks gestation provided greater reductions in preterm birth (RR 0·89, 95% CI 0·85-0·93; p=0·03). Generally, the survival and birth outcome effects of multiple micronutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micronutrient supplements did not significantly increase the risk of stillbirth or neonatal, 6-month, or infant mortality, neither overall or in any of the 26 examined subgroups. INTERPRETATION: Antenatal multiple micronutrient supplements improved survival for female neonates and provided greater birth-outcome benefits for infants born to undernourished and anaemic pregnant women. Early initiation in pregnancy and high adherence to multiple micronutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micronutrient supplements on infant health by maternal nutrition status and sex. FUNDING: None.

Maternal antenatal multiple micronutrient supplementation for long-term health benefits in children: a systematic review and meta-analysis.

BACKGROUND: Multiple micronutrient supplementation for pregnant women reduces low birth weight and has been recommended in low- and middle-income countries (LMICs) to improve child survival, growth and health. We aimed to review the evidence from long-term follow-up studies of multiple micronutrient supplementation beginning in the later first or second trimester. METHODS: We searched systematically for follow-up reports from all trials in a 2015 Cochrane review of multiple micronutrient supplementation in pregnancy. The intervention comprised three or more micronutrients and the comparison group received iron (60 mg) and folic acid (400 µg), where possible. Median gestation of commencement varied from 9 to 23 weeks. Primary outcomes were offspring mortality, height, weight and head circumference, presented as unadjusted differences in means or proportions (intervention minus control). Secondary outcomes included other anthropometry, body composition, blood pressure, and cognitive and lung function. RESULTS: We found 20 follow-up reports from nine trials (including 88,057 women recruited), six of which used the UNIMMAP supplement designed to provide recommended daily allowances. The age of follow-up ranged from 0 to 9 years. Data for mortality estimates were available from all trials. Meta-analysis showed no difference in mortality (risk difference -0.05 per 1000 livebirths; 95 % CI, -5.25 to 5.15). Six trials investigated anthropometry and found no difference at follow-up in weight-for-age z score (0.02; 95 % CI, -0.03 to 0.07), height-for-age z score (0.01; 95 % CI, -0.04 to 0.06), or head circumference (0.11 cm; 95 % CI, -0.03 to 0.26). No differences were seen in body composition, blood pressure, or respiratory outcomes. No consistent differences were seen in cognitive function scores. CONCLUSIONS: There is currently no evidence that, compared with iron and folic acid supplementation, routine maternal antenatal multiple micronutrient supplementation improves childhood survival, growth, body composition, blood pressure, respiratory or cognitive outcomes.

Reconstructing communities in cluster trials?

BACKGROUND: There is growing interest in the ethics of cluster trials, but no literature on the uncertainties in defining communities in relation to the scientific notion of the cluster in collaborative biomedical research. METHODS: The views of participants in a community-based cluster randomised trial (CRT) in Mumbai, India, were solicited regarding their understanding and views on community. We conducted two focus group discussions with local residents and 20 semi-structured interviews with different respondent groups. On average, ten participants took part in each focus group, most of them women aged 18-55. We conducted semi-structured interviews with ten residents (nine women and one man) lasting approximately an hour each and seven individuals (five men and two women) identified by residents as local leaders or decision-makers. In addition, we interviewed two Municipal Corporators (locally elected government officials involved in urban planning and development) and one representative of a political party located in a slum community. RESULTS: Residents' sense of community largely matched the scientific notion of the cluster, defined by the investigators as a geographic area, but their perceived needs were not entirely met by the trial. CONCLUSION: We examined whether the possibility of a conceptual mismatch between 'clusters' and 'communities' is likely to have methodological implications for a study or to lead to potential social disharmony because of the research interventions, arguing that it is important to take social factors into account as well as statistical efficiency when choosing the size and type of clusters and designing a trial. One method of informing such a design would be to use existing forums for community engagement to explore individuals' primary sense of community or social group and, where possible, to fit clusters around them. TRIAL REGISTRATION: ISRCTN Register: ISRCTN56183183 Clinical Trials Registry of India: CTRI/2012/09/003004 .

Blood pressure and the capacity-load model in 8-year-old children from Nepal: Testing the contributions of kidney size and intergenerational effects.

OBJECTIVES: Growth patterns in early life are increasingly linked with subsequent cardio-metabolic risk, but the underlying mechanisms require elucidation. We have developed a theoretical model of blood pressure, treating it as a function of homeostatic metabolic capacity, and antagonistic metabolic load. We sought to differentiate prenatal and postnatal components of metabolic capacity, and to identify intergenerational contributions to offspring capacity and load. METHODS: We followed up at 8 years a cohort of children originally recruited into a randomized trial of maternal micronutrient supplementation in pregnancy. Maternal anthropometry was measured at recruitment. Offspring anthropometry was measured at birth, 2 years and 8 years. Offspring blood pressure, kidney size, and body composition were measured at 8 years. Regression analysis was used to investigate potential associations of maternal phenotype, birth phenotype, and current body composition with kidney size and blood pressure. RESULTS: Blood pressure was positively associated with body fat, but negatively associated with birth weight and relative leg length. Kidney size was positively associated with birth weight but not with relative leg length. Adjusting for adiposity, blood pressure was independently negatively associated with birth weight, relative leg length, and kidney length. Maternal height and BMI predicted offspring size at birth and at 8 years, but not blood pressure. CONCLUSIONS: Our data provide support for the capacity-load model of blood pressure in Nepalese children. Fetal and postnatal growth and kidney dimensions all contribute to metabolic capacity. Maternal phenotype contributed to offspring capacity and load, but these associations did not propagate to blood pressure. Am. J. Hum. Biol. 28:555-565, 2016. © 2016 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc.

Using Observational Data to Estimate the Effect of Hand Washing and Clean Delivery Kit Use by Birth Attendants on Maternal Deaths after Home Deliveries in Rural Bangladesh, India and Nepal.

BACKGROUND: Globally, puerperal sepsis accounts for an estimated 8-12% of maternal deaths, but evidence is lacking on the extent to which clean delivery practices could improve maternal survival. We used data from the control arms of four cluster-randomised controlled trials conducted in rural India, Bangladesh and Nepal, to examine associations between clean delivery kit use and hand washing by the birth attendant with maternal mortality among home deliveries. METHODS: We tested associations between clean delivery practices and maternal deaths, using a pooled dataset for 40,602 home births across sites in the three countries. Cross-sectional data were analysed by fitting logistic regression models with and without multiple imputation, and confounders were selected a priori using causal directed acyclic graphs. The robustness of estimates was investigated through sensitivity analyses. RESULTS: Hand washing was associated with a 49% reduction in the odds of maternal mortality after adjusting for confounding factors (adjusted odds ratio (AOR) 0.51, 95% CI 0.28-0.93). The sensitivity analysis testing the missing at random assumption for the multiple imputation, as well as the sensitivity analysis accounting for possible misclassification bias in the use of clean delivery practices, indicated that the association between hand washing and maternal death had been over estimated. Clean delivery kit use was not associated with a maternal death (AOR 1.26, 95% CI 0.62-2.56). CONCLUSIONS: Our evidence suggests that hand washing in delivery is critical for maternal survival among home deliveries in rural South Asia, although the exact magnitude of this effect is uncertain due to inherent biases associated with observational data from low resource settings. Our findings indicating kit use does not improve maternal survival, suggests that the soap is not being used in all instances that kit use is being reported.

Effects of antenatal multiple micronutrient supplementation on lung function in mid-childhood: follow-up of a double-blind randomised controlled trial in Nepal.

A randomised trial of prenatal multiple micronutrient supplementation in Nepalese women increased birthweight and weight at 2 years of age in offspring, compared to those born to mothers who only received iron and folic acid supplements. Further follow-up of this cohort provided an opportunity to investigate the effect of antenatal multiple micronutrients on subsequent lung function by measuring spirometry at 7-9 years of age in C: hildren born during the trial. 841 children (80% of the cohort) were seen at mean±sd 8.5±0.4 years. Technically successful spirometry results were obtained in 793 (94.3%) children, 50% of whom had been randomised to micronutrient supplementation. Background characteristics, including anthropometry, were similar in the two allocation groups. Lung function was also similar, mean (95% CI) difference in z-scores (supplementation minus control) was -0.08 (-0.19-0.04), -0.05 (-0.17-0.06) and -0.04 (-0.15-0.07) for forced expiratory volume in 1 s (FEV1), forced vital capacity and FEV1/FVC, respectively. Compared with healthy white children, FEV1 and FVC in the "healthy" Nepalese children were ∼1 (∼13%) z-score lower, with no difference in FEV1/FVC. We conclude that, compared with routine iron and folic acid, multiple micronutrient supplementation during pregnancy has no effect on spirometric lung function in Nepalese children at 8.5 years of age.

Effect of antenatal multiple micronutrient supplementation on anthropometry and blood pressure in mid-childhood in Nepal: follow-up of a double-blind randomised controlled trial.

BACKGROUND: In 2002-04, we did a randomised controlled trial in southern Nepal, and reported that children born to mothers taking multiple micronutrient supplements during pregnancy had a mean birthweight 77 g greater than children born to mothers taking iron and folic acid supplements. Children born to mothers in the study group were a mean 204 g heavier at 2·5 years of age and their systolic blood pressure was a mean 2·5 mm Hg lower than children born to mothers in the control group. We aimed to follow up the same children to mid-childhood (age 8·5 years) to investigate whether these differences would be sustained. METHODS: For this follow-up study, we identified children from the original trial and measured anthropometry, body composition with bioelectrical impedance (with population-specific isotope calibration), blood pressure, and renal dimensions by ultrasound. We documented socioeconomic status, household food security, and air pollution. Main outcomes of the follow-up at 8 years were Z scores for weight-for-age, height-for-age, and body-mass index (BMI)-for-age according to WHO Child Growth Standards for children aged 5-19 years, and blood pressure. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN88625934. FINDINGS: Between Sept 21, 2011, and Dec 7, 2012, we assessed 841 children (422 in the control group and 419 in the intervention group). Unadjusted differences (intervention minus control) in Z scores were 0·05 for weight-for-age (95% CI -0·09 to 0·19), 0·02 in height-for-age (-0·10 to 0·15), and 0·04 in BMI-for-age (-0·09 to 0·18). We recorded no difference in blood pressure. Adjusted differences were similar for all outcomes. INTERPRETATION: We recorded no differences in phenotype between children born to mothers who received antenatal multiple micronutrient or iron and folate supplements at age 8·5 years. Our findings did not extend to physiological differences or potential longer-term effects. FUNDING: The Wellcome Trust.

Exploring the first delay: a qualitative study of home deliveries in Makwanpur district Nepal.

BACKGROUND: In many low-income countries women tend to deliver at home, and delays in receiving appropriate maternal care can be fatal. A contextual understanding of these delays is important if countries are to meet development targets for maternal health. We present qualitative research with women who delivered at home in rural Nepal, to gain a contemporary understanding of the context where we are testing the effectiveness of an intervention to increase institutional deliveries. METHODS: We purposively sampled women who had recently delivered at home and interviewed them to explore their reasons for home delivery. Interviews were recorded, transcribed and analysed using thematic content analysis. We used the 'delays' model discussed in the literature to frame our analysis. RESULTS: Usually a combination of factors prevented women from delivering in health institutions. Many women were aware of the benefits of institutional delivery yet their status in the home restricted their access to health facilities. Often they did not wish to bring shame on their family by going against their wishes, or through showing their body in a health institution. They often felt unable to demand the organisation of transportation because this may cause financial problems for their family. Some felt that government incentives were insufficient. Often, a lack of family support at the time of delivery meant that women delivered at home. Past bad experience, and poor quality health services, also prevented women from having an institutional delivery. CONCLUSIONS: Formative research is important to develop an understanding of local context. Sociocultural issues, perceived accessibility of health services, and perceived quality of care were all important barriers preventing institutional delivery. Targeting one factor alone may not be effective in increasing institutional deliveries. Our intervention encourages communities to develop local responses to address the factors preventing institutional delivery through women's groups and improved health facility management. We will monitor perceptions of health services over time to help us understand the effectiveness of the intervention.

Understanding psychological distress among mothers in rural Nepal: a qualitative grounded theory exploration.

BACKGROUND: There is a large burden of psychological distress in low and middle-income countries, and culturally relevant interventions must be developed to address it. This requires an understanding of how distress is experienced. We conducted a qualitative grounded theory study to understand how mothers experience and manage distress in Dhanusha, a low-resource setting in rural Nepal. We also explored how distressed mothers interact with their families and the wider community. METHODS: Participants were identified during a cluster-randomised controlled trial in which mothers were screened for psychological distress using the 12-item General Health Questionnaire (GHQ-12). We conducted 22 semi-structured interviews with distressed mothers (GHQ-12 score ≥ 5) and one with a traditional healer (dhami), as well as 12 focus group discussions with community members. Data were analysed using grounded theory methods and a model was developed to explain psychological distress in this setting. RESULTS: We found that distress was termed tension by participants and mainly described in terms of physical symptoms. Key perceived causes of distress were poor health, lack of sons, and fertility problems. Tension developed in a context of limited autonomy for women and perceived duty towards the family. Distressed mothers discussed several strategies to alleviate tension, including seeking treatment for perceived physical health problems and tension from doctors or dhamis, having repeated pregnancies until a son was delivered, manipulating social circumstances in the household, and deciding to accept their fate. Their ability to implement these strategies depended on whether they were able to negotiate with their in-laws or husbands for resources. CONCLUSIONS: Vulnerability, as a consequence of gender and social disadvantage, manifests as psychological distress among mothers in Dhanusha. Screening tools incorporating physical symptoms of tension should be envisaged, along with interventions to address gender inequity, support marital relationships, and improve access to perinatal healthcare.

Association between clean delivery kit use, clean delivery practices, and neonatal survival: pooled analysis of data from three sites in South Asia.

BACKGROUND: Sepsis accounts for up to 15% of an estimated 3.3 million annual neonatal deaths globally. We used data collected from the control arms of three previously conducted cluster-randomised controlled trials in rural Bangladesh, India, and Nepal to examine the association between clean delivery kit use or clean delivery practices and neonatal mortality among home births. METHODS AND FINDINGS: Hierarchical, logistic regression models were used to explore the association between neonatal mortality and clean delivery kit use or clean delivery practices in 19,754 home births, controlling for confounders common to all study sites. We tested the association between kit use and neonatal mortality using a pooled dataset from all three sites and separately for each site. We then examined the association between individual clean delivery practices addressed in the contents of the kit (boiled blade and thread, plastic sheet, gloves, hand washing, and appropriate cord care) and neonatal mortality. Finally, we examined the combined association between mortality and four specific clean delivery practices (boiled blade and thread, hand washing, and plastic sheet). Using the pooled dataset, we found that kit use was associated with a relative reduction in neonatal mortality (adjusted odds ratio 0.52, 95% CI 0.39-0.68). While use of a clean delivery kit was not always accompanied by clean delivery practices, using a plastic sheet during delivery, a boiled blade to cut the cord, a boiled thread to tie the cord, and antiseptic to clean the umbilicus were each significantly associated with relative reductions in mortality, independently of kit use. Each additional clean delivery practice used was associated with a 16% relative reduction in neonatal mortality (odds ratio 0.84, 95% CI 0.77-0.92). CONCLUSIONS: The appropriate use of a clean delivery kit or clean delivery practices is associated with relative reductions in neonatal mortality among home births in underserved, rural populations.

Effects of antenatal multiple micronutrient supplementation on children's weight and size at 2 years of age in Nepal: follow-up of a double-blind randomised controlled trial.

BACKGROUND: The negative effects of low birthweight on the later health of children in developing countries have been well studied. However, undertaking programmes to address this issue can be difficult since there is no simple correlation between increasing birthweight and improving child health. In 2005, we published results of a randomised controlled trial in Nepal, in which 1200 women received either iron and folic acid or a supplement that provided the recommended daily allowance of 15 vitamins and minerals, over the second and third trimesters of pregnancy. Here, we report on 2-3 years' follow-up of children born during the trial. METHODS: We visited children at home and obtained data for the primary outcomes of weight and height, for childhood illnesses, and maternal blood haemoglobin. The study is registered as an International Standard Randomised Controlled Trial, number ISRCTN88625934. FINDINGS: Between December, 2005, and December, 2006, we assessed 917 children (455 controls, 462 intervention) at a mean age of 2.5 years. Mean birthweight had been 77 g (95% CI 24-130) greater in the micronutrient group than in controls. At 2.5 years old, controls weighed a mean of 10.7 kg (SD 1.38), and those in the intervention group 10.9 kg (SD 1.54). Children of women who had taken multiple micronutrient supplements during pregnancy were a mean 204 g (95% CI 27-381) heavier than controls. They also had greater measurements than controls in the circumference of the head (2.4 mm [95% CI 0.6-4.3]), chest (3.2 mm [0.4-6.0]), and mid-upper arm (2.4 mm [1.1-3.7]), and in triceps skinfold thickness (2.0 mm [0.0-0.4]). Systolic blood pressure was slightly lower in the intervention group (2.5 mm Hg [0.5-4.6]). INTERPRETATION: In a poor population, the effects of maternal multiple micronutrient supplementation on the fetus persisted into childhood, with increases in both weight and body size. These increases were small, however, since those exposed to micronutrients had an average of 2% higher weight than controls. The public-health implications of changes in weight and blood pressure need to be clarified through further follow-up.

Effect of multiple micronutrient supplementation during pregnancy on inflammatory markers in Nepalese women.

BACKGROUND: Multiple micronutrient supplementation of Nepalese women during pregnancy is associated with a significant increase in birth weight. OBJECTIVE: We tested the hypothesis that improved birth weight in infants of mothers supplemented with micronutrients is associated with a decrease in inflammatory responses and an increase in the production of T helper 1 cells and T helper 2 cells. DESIGN: The study was embedded in a randomized controlled trial of 15 micronutrients, compared with iron-folate supplementation (control), given during pregnancy with the aim of increasing birth weight. Blood samples were collected at 32 wk of gestation, 12-20 wk after supplementation began, for the measurement of inflammatory markers. Breast-milk samples were collected 1 mo after delivery for the measurement of the ratio of milk sodium to potassium (milk Na:K). In an opportunistically selected subgroup of 70 women, mitogen-stimulated cytokine production was measured ex vivo in whole blood. RESULTS: Blood eosinophils; plasma concentrations of the acute phase reactants C-reactive protein, alpha(1)-acid glycoprotein (AGP), neopterin, and ferritin; milk Na:K; and the production of interleukin (IL) 10, IL-4, interferon gamma, and tumor necrosis factor alpha in whole blood did not differ significantly between the supplemented and control groups. Plasma C-reactive protein and AGP were higher in women who had a preterm delivery, and AGP was higher in women who delivered a low-birth-weight term infant than in women who delivered a normal-birth-weight term infant. CONCLUSIONS: The results indicate an association between systemic inflammation in late pregnancy and compromised delivery outcome in Nepalese women but do not support the hypothesis that multiple micronutrient supplementation changes cytokine production or inflammatory markers.

Effects of antenatal multiple micronutrient supplementation on birthweight and gestational duration in Nepal: double-blind, randomised controlled trial.

BACKGROUND: Neonatal mortality is the biggest contributor to global mortality of children younger than 5 years, and low birthweight is a crucial underlying factor. We tested the hypotheses that antenatal multiple micronutrient supplementation would increase infant birthweight and gestational duration. METHODS: We did a double-blind, randomised controlled trial in Dhanusha district, Nepal. Women attending for antenatal care with singleton pregnancies at up to 20 weeks' gestation were invited to participate. Participants were randomly allocated either routine iron and folic acid supplements (control; n=600) or a multiple micronutrient supplement providing a recommended daily allowance of 15 vitamins and minerals (intervention; n=600). Supplementation began at a minimum of 12 weeks' gestation and continued until delivery. Primary outcome measures were birthweight and gestational duration. Analysis was by intention to treat. The study is registered as an International Standard Randomised Controlled Trial, number ISRCTN88625934. FINDINGS: Birthweight was available for 523/600 infants in the control group and 529/600 in the intervention group. Mean birthweight was 2733 g (SD 422) in the control group and 2810 g (453) in the intervention group, representing a mean difference of 77 g (95% CI 24-130; p=0.004) and a relative fall in the proportion of low birthweight by 25%. No difference was recorded in the duration of gestation (0.2 weeks [-0.1 to 0.4]; p=0.12), infant length (0.3 cm [-0.1 to 0.6]; p=0.16), or head circumference (0.2 cm [-0.1 to 0.4]; p=0.18). INTERPRETATION: In a poor community in Nepal, consumption of a daily supplement containing a recommended daily allowance of 15 micronutrients in the second and third trimesters of pregnancy was associated with increased birthweight when compared with a standard iron and folic acid preparation. The effects on perinatal morbidity and mortality need further comparisons between studies. Published online March 3, 2005 http://image.thelancet.com/extras/04art11045web.pdf.